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Departments of Physiology and Pharmacology and
Cell and Developmental Biology, Oregon Health and Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA
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Departments of Physiology and Pharmacology and
Cell and Developmental Biology, Oregon Health and Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA
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Departments of Physiology and Pharmacology and
Cell and Developmental Biology, Oregon Health and Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA
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Departments of Physiology and Pharmacology and
Cell and Developmental Biology, Oregon Health and Science University, 505 NW 185th Ave., Beaverton, OR 97006, USA
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The great writer and polyglot, W Somerset Maugham said, ‘I’ll give you my opinion of the human race in a nutshell...their heart’s in the right place, but their head is a thoroughly inefficient organ.’ If his words are applied to trafficking of the human pituitary gonadotropin-releasing hormone receptor, it turns out that he was more right than he knew. Paradoxically, the inefficiency of receptor trafficking to the plasma membrane can bring regulatory advantages to cells. Understanding the mechanism by which cells recognize correctly folded proteins in health and disease opens doors to new therapeutic approaches and provides a more accurate view of mechanisms of normal cell function than is presently available.
Research Unit in Reproductive Medicine, Hospital de Ginecobstetricia ‘Luis Castelazo Ayala’, IMSS, Río Magdalena 286-6 *piso, México 10101, Mexico
The Salk Institute, La Jolla, California 92037, USA
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Research Unit in Reproductive Medicine, Hospital de Ginecobstetricia ‘Luis Castelazo Ayala’, IMSS, Río Magdalena 286-6 *piso, México 10101, Mexico
The Salk Institute, La Jolla, California 92037, USA
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Research Unit in Reproductive Medicine, Hospital de Ginecobstetricia ‘Luis Castelazo Ayala’, IMSS, Río Magdalena 286-6 *piso, México 10101, Mexico
The Salk Institute, La Jolla, California 92037, USA
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Research Unit in Reproductive Medicine, Hospital de Ginecobstetricia ‘Luis Castelazo Ayala’, IMSS, Río Magdalena 286-6 *piso, México 10101, Mexico
The Salk Institute, La Jolla, California 92037, USA
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Research Unit in Reproductive Medicine, Hospital de Ginecobstetricia ‘Luis Castelazo Ayala’, IMSS, Río Magdalena 286-6 *piso, México 10101, Mexico
The Salk Institute, La Jolla, California 92037, USA
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Research Unit in Reproductive Medicine, Hospital de Ginecobstetricia ‘Luis Castelazo Ayala’, IMSS, Río Magdalena 286-6 *piso, México 10101, Mexico
The Salk Institute, La Jolla, California 92037, USA
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GnRH agonists or antagonists are currently utilized as therapeutic agents in a number of diseases. A side-effect of prolonged treatment with GnRH analogues is hypoestrogenism. In this study, we tested the in vitro potency of different GnRH analogues originally found to be partial agonists (i.e. analogues with decreased efficacy for activating or stimulating their cognate receptor) as well as novel analogues, to identify compounds that might potentially be useful for partial blockade of gonadotrophin release. Cultured COS-7 cells transiently expressing the rat or human GnRH receptor (GnRHR) were exposed to increasing concentrations (10−8 to 10−5 M) of GnRH analogues (c(4–10)[Asp4,DNal6,Dpr10]-GnRH; c(4–10) [Dpr4,DNal6,Asp10]-GnRH; c(4–10)[Cys4,10,DNal6]-GnRH; c[Eaca1,DNal6]-GnRH; c[Gly1,DNal6]-GnRH; c[βAla1,DTrp6]-GnRH; c[Dava1,DNal6]-GnRH; c[Gaba1, DNal6]-GnRH), and the ability of these analogues to provoke or antagonize GnRH-stimulated inositol phosphate production was assessed.
With both human and rat GnRHRs, c[Eaca1,DNal6]-GnRH, c[Gly1,DNal6]-GnRH, c[βAla1,DTrp6]-GnRH and c[Dava1,DNal6]-GnRH exhibited partial agonist activity (35–87% of the maximal efficacy shown by 10−6 M GnRH), whereas c[Gaba1,DNal6]-GnRH behaved as a partial agonist with the human GnRHR and as full agonist with the rat GnRHR. c(4–10)[Asp4, DNal6,Dpr10]-GnRH and c(4–10)[Dpr4,DNal6,Asp10]-GnRH exhibited full antagonist activity with both GnRHRs, and c(4–10) [Cys4,10,DNal6]-GnRH was a weak, partial agonist with the human GnRHR and a full antagonist with the rat GnRHR. With the exception of c[Gaba1,DNal6]-GnRH stimulation of the human GnRHR, and c[Dava1,DNal6]-GnRH and c[Gaba1, DNal6]-GnRH stimulation of the rat GnRHR, all partial agonists also exhibited antagonist activity in the presence of the exogenous full agonist.
The results demonstrate that structurally similar analogues display variable potencies and efficacies in vitro for a specific GnRHR as well as for the human versus the rat GnRHR. Their ultimate in vivo usefulness to treat clinical conditions in which complete suppression of gonadotroph activity is not required remains to be investigated.
